Epithelial-mesenchymal Transition In Endometriosis Research Articles

Loss of KLF15 impairs endometrial receptivity by inhibiting EMT in endometriosis.

The impaired endometrial receptivity is a major factor contributing to infertility in patients with endometriosis (EM), but the underlying mechanism remains unclear. Our study aimed to investigate the role of Kruppel-like factor 15 (KLF15) in endometrial receptivity and its regulation in EM. We observed a significant decrease in KLF15 expression in the mid-secretory epithelial endometrial cells of EM patients compared to normal females without EM. To confirm the role of KLF15 in endometrial receptivity, we found a significantly reduced KLF15 expression and a significant decrease in embryo implantation number in the rat model via uterine horn infection with siRNA. This highlights the importance of KLF15 as a regulator receptivity. Furthermore, through ChIP-qPCR, we discovered that the progesterone receptor (PR) directly binds to KLF15 promoter regions, indicating that progesterone resistance may mediate the decrease in KLF15 expression in EM patients. Additionally, we found that the mid-secretory endometrium of EM patients exhibited impaired epithelial-mesenchymal transition (EMT). Knockdown of KLF15 upregulated E-cadherin and downregulated vimentin expression, leading to inhibited invasiveness and migration of Ishikawa cells. Overexpression KLF15 promotes EMT, invasiveness, and migration ability, and increases the attachment rate of JAR cells to Ishikawa cells. Through RNA-seq analysis, we identified TWIST2 as a downstream gene of KLF15. We confirmed that KLF15 directly binds to the promoter region of TWIST2 via ChIP-qPCR, promoting epithelial cell EMT during the establishment of endometrial receptivity. Our study reveals the involvement of KLF15 in the regulation of endometrial receptivity and its downstream effects on EMT. These findings provide valuable insights into potential therapeutic approaches for treating non-receptive endometrium in patients with EM.

RETRACTED: Overexpressed miR-106b-5p promotes epithelial-mesenchymal transition in endometriosis by targeting PTEN

The miRNA miR-106b-5p expression is elevated in endometriotic lesions. This study aimed to detect miR-106b-5p expression in human endometrial stromal cells and explore the molecular mechanisms regulating proliferation, migration, and epithelial-mesenchymal transition (EMT) of these cells. Cell proliferation, migration, and EMT were compared after miR-106b-5p upregulation. The downstream target of miR-106b-5p was verified using bioinformatic, luciferase reporter, and rescue assays. The relationship between miR-106b-5p and the target genes was also analyzed. Results showed that the expression of miR-106b-5p in endometriotic lesions was higher than that in non-lesion tissues. Furthermore, upregulation of miR-106b-5p promoted the proliferation, migration, and EMT of human endometrial stromal cells. Additionally, phosphatase and tensin homolog ten (PTEN) was found to be negatively correlated with miR-106b-5p expression. Low expression levels of PTEN were significantly correlated with cell proliferation, migration, and EMT. High PTEN expression could rescue the effect of miR-106b-5p on cell capacity. In conclusion, miR-106b-5p modified human endometrial stromal cell function by sponging PTEN. These findings indicate that inhibition of miR-106b-5p may be an effective therapeutic strategy for endometriosis.

CircATRNL1 increases acid-sensing ion channel 1 to advance epithelial-mesenchymal transition in endometriosis by binding to microRNA-103a-3p

Circular RNA ATRNL1 (circATRNL1) has been implicated in epithelial-mesenchymal transition (EMT) during endometriosis. Given the existing literature and our predictions through starBase in this research, it was assumed that circATRNL1 might orchestrate the microRNA (miR)-103a-3p/acid-sensing ion channel 1 (ASIC1) axis to control EMT in endometriosis. To verify our hypothesis, we detect circATRNL1, miR-103a-3p, and ASIC1 expression in endometrial cancer cells (HEC-B, AN3-CA, KLE, HEC1-A, and Ishikawa). Ishikawa cells with the highest circATRNL1 level were selected as subjects, where circATRNL1, miR-103a-3p, or ASIC1 expression was knocked down. Scratch and Transwell assays were applied to assess cell migration and invasion, and CCK-8 and colony formation assays to detect cell proliferation. Western blot was used to measure E-cadherin, N-cadherin, Vimentin, and Slug expression to evaluate the EMT state. Furthermore, the binding of miR-103a-3p to circATRNL1 or ASIC1 was validated by luciferase reporter assay. CircATRNL1 and ASIC1 were upregulated but miR-103a-3p was downregulated in endometrial cancer cells. Mechanistically, circATRNL1 bound to miR-103a-3p to upregulate a target gene of miR-103a-3p, ASIC1. CircATRNL1 silencing contributed to the decline of proliferation, invasion, migration, and EMT in Ishikawa cells, while miR-103a-3p inhibitor reversed those changes. In addition, the EMT process was aggravated when miR-103a-3p was inhibited and this process was suppressed by silencing ASIC1 in the presence of downregulated miR-101a-3p. Our study supported that circATRNL1 might be a novel therapeutic candidate target for endometriosis treatment and provided unique insights into the molecular basis concerning the pathogenesis of endometriosis.

Circular RNA circZFPM2 promotes epithelial-mesenchymal transition in endometriosis by regulating miR-205-5p/ZEB1 signalling pathway

Endometriosis is a debilitating gynecological disease affecting millions of women worldwide, but its exact pathogenesis remains unclear. Circular RNAs (circRNAs) have been demonstrated to be important regulators in multiple diseases. Nonetheless, the potential regulatory mechanism of aberrant circRNA expression in endometriosis has been elusive. The up-regulated circZFPM2 in ectopic endometrial tissues was previously screened by circRNA high-throughput sequencing and was furtherly validated by quantitative real time reverse transcriptase polymerase chain reaction (RT-qPCR). Overexpression of circZFPM2 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in Ishikawa and End1/E6E7 cells, whereas silencing circZFPM2 produced the opposite effect. Luciferase reporter assays validated that circZFPM2 could directly target miR-205-5p and miR-205-5p target ZEB1. RT-qPCR results showed that miR-205-5p was underexpressed while ZEB1 was overexpressed in ectopic endometrial tissues compared with their expression in eutopic endometria and non-endometriosis control endometria. The expression level of miR-205-5p was inversely proportional and that of ZEB1 was directly proportional with the proliferative, migrative, and invasive ability of endometrial cells. Further in vitro investigation indicated that miR-205-5p could inhibit EMT by targeting ZEB1. Subsequent rescue experiments confirmed that circZFPM2 could induce EMT and promote cell proliferation, migration, and invasion cascades through the miR-205-5p /ZEB1 signaling pathway. Conclusively, circZFPM2 may present a promising biomarker in the diagnosis and treatment of endometriosis.

Upregulation of the long noncoding RNA UBOX5 antisense RNA 1 (UBOX5-AS1) under hypoxic conditions promotes epithelial-mesenchymal transition in endometriosis.

BackgroundEndometriosis is a debilitating gynecological condition that manifests many common malignant features, including migration and invasion. Hypoxia is a hallmark of endometriosis, characterized by endometrial cell metastasis via epithelial-mesenchymal transition (EMT). The long noncoding RNA (lncRNA) UBOX antisense RNA 1 (UBOX5-AS1) has been shown to be upregulated in ovarian endometriosis. However, the molecular mechanisms and biological functions of lncRNA UBOX5-AS1 in hypoxia-induced endometriosis EMT remain to be explored.MethodsNormal, eutopic, and ectopic endometrium from ovarian endometriosis tissues were collected, and the expressions of hypoxia inducible factor (HIF)-1α, lncRNA UBOX5-AS1, E-cadherin, and vimentin were analyzed by quantitative real time polymerase chain reaction (qRT-PCR) and western blotting analysis. Primary human endometrial epithelial cells and human endometrial epithelial adenocarcinoma Ishikawa cell lines were cultured under hypoxic conditions, and western blotting analysis and immunocytochemistry were performed to investigate hypoxia-induced EMT. Moreover, HIF-1α and lncRNA UBOX5-AS1 were overexpressed and knocked down in endometrial epithelial cells to explore the role and mechanisms of lncRNA UBOX5-AS1 in hypoxia-triggered EMT. The migration and invasion potential of human endometrial epithelial cells was detected by Transwell migration/invasion assays.ResultsIn ovarian endometriosis, the expression of hypoxia-inducible factor-1α (HIF-1α) and lncRNA UBOX5-AS1 were significantly increased, and this was accompanied by EMT. Furthermore, endometrial epithelial cells cultured under hypoxic conditions exhibited elevated lncRNA UBOX5-AS1 expression, as well as migration, invasion, and an EMT-like phenotype. This data indicated that HIF-1α signaling was crucial for hypoxia-induced lncRNA UBOX5-AS1 upregulation and the EMT process. Moreover, downregulation of lncRNA UBOX5-AS1 inhibited the hypoxia-induced EMT and attenuated cell migration and invasion.ConclusionsThe present research demonstrated that hypoxia upregulated the expression of lncRNA UBOX5-AS1 via HIF-1α-dependent signaling. The increased expression of lncRNA UBOX5-AS1 plays a vital role in mediating the hypoxia-regulated EMT and invasiveness of endometriosis, suggesting that lncRNA UBOX5-AS1 may be an important potential therapeutic target for endometriosis.

TET1 may contribute to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis.

BackgroundEndometriosis (EMs) is a non-malignant gynecological disease, whose pathogenesis remains to be clarified. Recent studies have found that hypoxia induces epithelial-mesenchymal transition (EMT) as well as epigenetic modification in EMs. However, the relationship between EMT and demethylation modification under hypoxia status in EMs remains unknown.MethodsThe expression of N-cadherin, E-cadherin and TET1 in normal endometria, eutopic endometria and ovarian endometriomas was assessed by immunohistochemistry and immunofluorescence double staining. 5-hmC was detected by fluorescence-based ELISA kit using a specific 5-hmC antibody. Overexpression and inhibition of TET1 or hypoxia-inducible factor 2α (HIF-2α) were performed by plasmid and siRNA transfection. The expression of HIF-2α, TET1 and EMT markers in Ishikawa (ISK) cells (widely used as endometrial epithelial cells) was evaluated by western blotting. The interaction of HIF-2α and TET1 was analyzed by chromatin immunoprecipitation.ResultsDemethylation enzyme TET1 (ten-eleven translocation1) was elevated in glandular epithelium of ovarian endometrioma, along with the activation of EMT (increased expression of N-cadherin, and decreased expression of E-cadherin) and global increase of epigenetic modification marker 5-hmC(5-hydroxymethylcytosine). Besides, endometriosis lesions had more TET1 and N-cadherin co-localized cells. Further study showed that ISK cells exhibited enhanced EMT, and increased expression of TET1 and HIF-2α under hypoxic condition. Hypoxia-induced EMT was partly regulated by TET1 and HIF-2α. HIF-2α inhibition mitigated TET1 expression changes provoked by hypoxia.ConclusionsHypoxia induces the expression of TET1 regulated by HIF-2α, thus may promote EMT in endometriosis.

Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis

Background: Endometriosis is a frequently occurring disease in women, which seriously affects their quality of life. However, its etiology and pathogenesis are still unclear. Methods: To identify key genes/pathways involved in the pathogenesis of endometriosis, we recruited 3 raw microarray datasets (GSE11691, GSE7305, and GSE12768) from Gene Expression Omnibus database (GEO), which contain endometriosis tissues and normal endometrial tissues. We then performed in-depth bioinformatic analysis to determine differentially expressed genes (DEGs), followed by gene ontology (GO), Hallmark pathway enrichment and protein-protein interaction (PPI) network analysis. The findings were further validated by immunohistochemistry (IHC) staining in endometrial tissues from endometriosis or control patients. Results: We identified 186 DEGs, of which 118 were up-regulated and 68 were down-regulated. The most enriched DEGs in GO functional analysis were mainly associated with cell adhesion, inflammatory response, and extracellular exosome. We found that epithelial-mesenchymal transition (EMT) ranked first in the Hallmark pathway enrichment. EMT may potentially be induced by inflammatory cytokines such as CXCL12. IHC confirmed the down-regulation of E-cadherin (CDH1) and up-regulation of CXCL12 in endometriosis tissues. Conclusions: Utilizing bioinformatics and patient samples, we provide evidence of EMT in endometriosis. Elucidating the role of EMT will improve the understanding of the molecular mechanisms involved in the development of endometriosis.

The role of miR-34c-5p/Notch in epithelial-mesenchymal transition (EMT) in endometriosis

Endometriosis, a common benign gynecological disease, has the growth characteristics of malignant tumors, however, the pathogenesis of this disease remains unclear. It is well known that micro ribonucleic acids (miRNAs) are involved in epithelial-mesenchymal transition (EMT), associated with the development of endometriosis. This study investigated the role of a specific miRNA, miR-34c-5p, in endometriosis. High-throughput sequencing (HTS) showed that miR-34c-5p expression was reduced in ectopic endometrium (ecEM) in patients from Northeast Asia with ovarian endometriosis. A wound healing assay and a transwell invasion assay showed that miR-34c-5p inhibits the invasion and migration of Ishikawa and End1/E6E7 endocervical cells. Dual luciferase gene reporter assays revealed that miR-34c-5p specifically targets Notch1 3 ‘UTR, and Western blot analyses showed that miR-34c-5p promotes E-cadherin expression but inhibits Notch1, N-cadherin and vimentin expression in Ishikawa and End1/E6E7 cell lines. These results were reversed following knockdown of miR-34c-5p. Using quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot analyses, there was a significant reduction in the expression of Notch1 in ecEM compared with eutopic endometrium (euEM). The results of this study indicate that miR-34c-5p inhibits the progression of EMT and cell invasion and migration by targeting the Notch signaling pathway, specifically, Notch1. The findings of this study provide unique insights into the development of EMT in endometriosis and novel, potential therapeutic targets

E2 -mediated EMT by activation of β-catenin/Snail signalling during the development of ovarian endometriosis.

Endometriosis is an oestrogen‐dependent disease, and epithelial‐mesenchymal transition (EMT) is involved in the process of endometriosis. Whether oestrogen could induce EMT in endometriosis remains largely unknown. Here, we reported that up‐regulated expression of EMT markers in ovarian chocolate cyst is accompanied by high expression 17β‐hydroxysteroid dehydrogenase 1 (17β‐HSD1), and exposure of primary human endometrial epithelial cells to oestradiol conditions could promote EMT occurrence and activate both β‐catenin and Snail signalling. Furthermore, we found nuclear β‐catenin and Snail expression was closely linked in ovarian endometriosis, and β‐catenin knockdown abrogated oestrogen‐induced Snail mediated EMT in vitro. This is due to that β‐catenin/ TCF‐3 could bind to Snail promoter and activate its transcription. These results suggested that β‐catenin signalling functions as the Snail activator and plays a critical role in oestradiol‐induced EMT in endometriosis.

MicroRNA-126-5p downregulates BCAR3 expression to promote cell migration and invasion in endometriosis

PurposeEndometriosis (EMs) is an estrogen-dependent multifactorial disease. Inhibition of estrogen in endometrial cells contributes to their failure to form lesions in ectopic sites. However, whether reducing or suppressing the inhibitory effect of estrogen results in the establishment of ectopic lesions remains unclear. The BCAR3 gene induces estrogen resistance in estrogen-dependent breast cancer cells and promotes cell migration, invasion, and epithelial-mesenchymal transition (EMT). However, the expression of BCAR3 in endometriosis and its effect on endometrial cell function and the anti-estrogen effect of endometriosis have not been reported. These issues are addressed in the present study. MethodsThe study included 32 cases of ectopic endometrium and eutopic endometrium in patients with endometriosis and 31 cases of normal endometrium as controls. The expression of BCAR3 and microRNA (miR)-126-5p was detected by real-time PCR, immunohistochemistry, and western blotting. The effects of BCAR3 and miR-126-5p on the morphology and biological behavior of eutopic endometrial cells were verified using lentivirus overexpression and a vector knockdown model, the CCK-8 assay, Transwell experiments, and estrogen intervention experiments using primary cultures of epithelial and stromal cells. ResultsThe BCAR3 gene was highly expressed in ectopic endometrium and the eutopic endometrium of patients with endometriosis, and the expression level was higher in stage III-IV patients than in stage I-II patients. In vitro cell experiments showed that miR-126-5p negatively regulated the expression of BCAR3 and its effect on the migration and invasion of stromal cells. Low expression of miR-126-5p and high expression of BCAR3 promoted endometriosis stromal cell migration and invasion. Assessment of EMT in endometriosis compared with eutopic endometrium showed that the expression of vimentin was significantly increased and the expression of E-cadherin was significantly decreased in ectopic endometrium. Estrogen promoted EMT in eutopic endometrial epithelial cells and this effect was reversed by estrogen inhibitors. BCAR3 had no direct effect on EMT and did not act synergistically with estrogen on promoting EMT. ConclusionmiR-126-5p negatively regulated BCAR3 expression in eutopic endometriosis, enhanced the migration and invasion of endometrial cells, and promoted the occurrence of endometriosis. BCAR3 did not induce EMT and had no synergistic effect with estrogen, but its inhibition of anti-estrogen function may provide new insight into the mechanism of local estrogen action in endometriosis.

Downregulated circular RNA hsa_circ_0067301 regulates epithelial-mesenchymal transition in endometriosis via the miR-141/Notch signaling pathway

Endometriosis is a common gynecologic disorder with enigmatic etiopathogenesis and is characterized by tumor-like biological behaviors. Epithelial-mesenchymal transition (EMT) has been recognized as a core mechanism of endometriosis. Recently, circular RNAs (circRNAs) have attracted considerable attention because they play an important role in the progression of cancer. However, little is known about the function of circRNAs in endometriosis. This study is intended to investigate the involvement of circRNAs and microRNAs in the process of EMT in ovarian endometriosis in vitro. We found that relative RNA levels of hsa_circ_0067301 and miR-141–5p were significantly reduced in ectopic endometrium when compared to control endometrium. Hsa_circ_0067301 knockdown could promote the proliferation and migration in Ishikawa and End1/E6E7 cells, concomitant with increased the relative protein expression against Notch-1, Hes-1, N-cadherin, and vimentin but reduced expression of E-cadherin. After co-transfection with the miR-141–5p inhibitor, the miR-141–5p that competes for binding to hsa_circ_0067301 was reduced, reversed EMT and partially restored the expression of Notch-1 and Hes-1. Results demonstrate the hsa_circ_0067301/miR-141–5p/Notch-1 axis plays an important regulatory role in the process of EMT in endometriosis. The study highlighted the importance of circRNAs in ovarian endometriosis and provided unique insights into the molecular basis concerning the pathogenesis of endometriosis.

Expression Profile Analysis of Circular RNAs in Ovarian Endometriosis by Microarray and Bioinformatics.

BackgroundEndometriosis is a common gynecologic disorder with enigmatic etiopathogenesis and is characterized by tumor-like biological behaviors. Recently, circular RNAs (circRNAs) have attracted considerable attention because they exert very important functions in the progression of human cancers. However, little is known about the functions and molecular mechanism of circRNAs in endometriosis.Material/MethodsA total of 20 patients with ovarian endometriosis and 4 normal endometrium from women free of endometriosis were included in this study. Ectopic endometrium tissues and paired eutopic endometrium tissues were collected from ovarian endometriosis patients. We assessed the expression profiles of circRNAs in endometriosis by microarray analysis. Expression of selected circRNAs in those tissues was detected by quantitative real-time PCR (qRT-PCR). Based on the target prediction, we constructed a circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network and elucidated circRNAs through Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses.ResultsWe detected 2237 circRNAs, differentially expressed among 3 groups, and then found 8 circRNAs that may be involved in the epithelial-mesenchymal transition process. The qRT-PCR validation suggested that circ_103470 and circ_101102 matched the microarray results. The functional analysis revealed 17 pathways, such as the mTOR signaling pathway, the Hippo signaling pathway, and the HIF-1 signaling pathway, which may be associated with the pathogenesis and development of endometriosis.ConclusionsIn general, our results suggest that 2 downregulated circRNAs (circ_103470 and circ_101102) may regulated epithelial-mesenchymal transition in endometriosis via miR-141-5p, which may be a promising therapeutic target in the future.

Lipoxin A4 Suppresses Estrogen-Induced Epithelial-Mesenchymal Transition via ALXR-Dependent Manner in Endometriosis.

Epithelial-mesenchymal transition (EMT) is essential for embryogenesis, fibrosis, and tumor metastasis. Aberrant EMT phenomenon has been reported in endometriotic tissues of patients with endometriosis (EM). In this study, we further investigated the molecular mechanism of which lipoxin A4 (LXA4) suppresses estrogen (E2)-induced EMT in EM. The EMT markers were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot in eutopic endometrial epithelial cells (EECs) or investigated by immunohistochemistry and qRT-PCR in endometriotic lesion of EM mice. The invasion and migration under different treatments were assessed by transwell assays with or without Matrigel. The messenger RNA (mRNA) and activities of matrix metalloproteinase 2 (MMP-2) and MMP-9 were determined by qRT-PCR and gelatin zymography, respectively. Luciferase reporter assay was used to measure the activity of zinc finger E-box binding homeobox 1(ZEB1) promoter. The level of E2 in endometriotic tissues was assessed by enzyme-linked immunosorbent assay. In eutopic EECs, stimulatory effects of E2 on EMT progress, migration, and invasion were all diminished by LXA4. Lipoxin A4 reduced E2-induced ZEB1 promoter activity. Lipoxin A4 also attenuated the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase induced by E2. Co-incubation with Boc-2 rather than DMF antagonized the influence of LXA4. Animal experiments showed that LXA4 inhibited the EMT progress, MMP expression, and proteinase activities of endometriotic lesion in an LXA4 receptor (ALXR) manner, which suppressed the progression of EM. ZEB1 mRNA expression was upregulated and well correlated with E2 level in human endometrium. Lipoxin A4 suppresses E2-induced EMT via ALXR-dependent manner in eutopic EECs, which reveals a novel biological effect of LXA4 in EM.

Reduced Expression of Eukaryotic Translation Initiation Factor 3 Subunit e and Its Possible Involvement in the Epithelial-Mesenchymal Transition in Endometriosis.

Epithelial-mesenchymal transition (EMT) is now well documented to be involved in the development of endometriosis through the promotion of invasion and fibrogenesis. To date, several factors have been reported to be involved in EMT in endometriosis. The eukaryotic translation initiation factor 3 subunit e (eIF3e) protein is a component of the multisubunit eIF3 complex essential for cap-dependent translation initiation. The aim of this study was to investigate whether eIF3e is involved in EMT in endometriosis. We recruited 40 premenopausal women (34.7 [6.8] years) with laparoscopically and histologically diagnosed ovarian endometriomas, and their ectopic endometrial tissue samples were collected after informed consent. As controls, endometrial tissue samples were obtained after informed consent from 40 premenopausal women, roughly age-matched (36.9 [6.4] years) and menstrual phase-matched with endometriosis group, who underwent surgery for benign gynecologic disorders or cervical intraepithelial neoplasia but without endometriosis, adenomyosis, or uterine fibroids. All tissue samples were subjected to immunohistochemistry analysis of eIF3e, transforming growth factor (TGF-β1), Snail, E-cadherin, vimentin, and proliferating cell nuclear antigen (PCNA). We found significantly reduced immunoreactivity against eIF3e and E-cadherin but elevated immunoreactivity against TGF-β1, Snail, vimentin, and PCNA in endometriotic epithelial cells when compared to that of control endometrium (all P values <.05). The eIF3e staining levels correlated negatively with that of TGF-β1 and Snail but positively with that of E-cadherin (all P values <.05). These data suggest that eIF3e downregulation may be involved in EMT in endometriosis, possibly through preferential translation of Snail. Future studies are warranted to confirm whether this is the mechanism.

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis.